Azabicyclononene derivatives

ABSTRACT

The invention relates to novel 9-azabicyclo[3.3.1]nonene derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.

The invention relates to novel compounds of the general formula I. Theinvention also concerns related aspects including processes for thepreparation of the compounds, pharmaceutical compositions containing oneor more compounds of formula I and especially their use as renininhibitors in cardiovascular events and renal insufficiency.Furthermore, these compounds can be regarded as inhibitors of otheraspartyl proteases and might therefore be useful as inhibitors ofplasmepsins to treat malaria and as inhibitors of Candida albicanssecreted aspartyl proteases to treat fungal infections.

In the renin-angiotensin system (RAS) the biologically activeangiotensin II (Ang II) is generated by a two-step mechanism. The highlyspecific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I),which is then further processed to Ang II by the less specificangiotensin-converting enzyme (ACE). Ang II is known to work on at leasttwo receptor subtypes called AT₁ and AT₂. Whereas AT₁ seems to transmitmost of the known functions of Ang II, the role of AT₂ is still unknown.

Modulation of the RAS represents a major advance in the treatment ofcardiovascular diseases. ACE inhibitors and AT₁ blockers have beenaccepted to treat hypertension (Waeber B. et al., “The renin-angiotensinsystem: role in experimental and human hypertension”, in Berkenhager W.H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier SciencePublishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5,247S). In addition, ACE inhibitors are used for renal protection(Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J.A. et al., Kidney International, 1994, 45, S156), in the prevention ofcongestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994,28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83)and myocardial infarction (Pfeffer M. A. et al., N. Engl. J. Med., 1992,327, 669).

The rationale to develop renin inhibitors is the specificity of renin(Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrateknown for renin is angiotensinogen, which can only be processed (underphysiological conditions) by renin. In contrast, ACE can also cleavebradykinin besides Ang I and can be by-passed by chymase, a serineprotease (Husain A., J. Hypertens., 1993, 11, 1155). In patientsinhibition of ACE thus leads to bradykinin accumulation causing cough(5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%)(Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234).Chymase is not inhibited by ACE inhibitors. Therefore, the formation ofAng II is still possible in patients treated with ACE inhibitors.Blockade of the AT₁ receptor (e.g. by losartan) on the other handoverexposes other AT-receptor subtypes to Ang II, whose concentration isdramatically increased by the blockade of AT₁ receptors. This may raiseserious questions regarding the safety and efficacy profile of AT₁receptor antagonists. In summary, renin inhibitors are not only expectedto be different from ACE inhibitors and AT₁ blockers with regard tosafety, but more importantly also with regard to their efficacy to blockthe RAS.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994,12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has beencreated with renin inhibitors because of their insufficient oralactivity due to their peptidomimetic character (Kleinert H. D.,Cardiovasc. Drugs, 1995, 9, 645). The clinical development of severalcompounds has been stopped because of this problem together with thehigh cost of goods. Only one compound containing four chiral centers hasentered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493;Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, metabolicallystable, orally bioavailable and sufficiently soluble renin inhibitorsthat can be prepared on a large scale are missing and sought. Recently,the first non-peptide renin inhibitors were described which show high invitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; PatentApplication WO97/09311; Märki H. P. et al., Il Farmaco, 2001, 56, 21).However, the development status of these compounds is not known.

The present invention relates to the identification of renin inhibitorsof a non-peptidic nature and of low molecular weight. Orally activerenin inhibitors of long duration of action which are active inindications beyond blood pressure regulation where the tissularrenin-chymase system may be activated leading to pathophysiologicallyaltered local functions such as renal, cardiac and vascular remodeling,atherosclerosis, and possibly restenosis are described.

The present invention describes non-peptidic renin inhibitors.

In particular, the present invention relates to novel compounds of thegeneral formula I,

whereinW is a six-membered, non benzofused, phenyl or heteroaryl ring,substituted by V in meta or para position;V represents a bond; —(CH₂)_(r)—; -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t)—;—(CH₂)_(s)-A-; —(CH₂)₂-A-(CH₂)_(u)—; -A-(CH₂)_(v)—B—;—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—B—;—CH₂—CH₂—CH₂-A-CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—CH₂—;—CH₂-A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—CH₂—B—; —CH₂—CH₂-A-CH₂—CH₂—B—;—O—CH₂—CH(OCH₃)—CH₂—O—; —O—CH₂—CH(CH₃)—CH₂—O—; —O—CH₂—CH(CF₃)—CH₂—O—;—O—CH₂—C(CH₃)₂—CH₂—O—; —O—CH₂—C(CH₃)₂—O—; —O—C(CH₃)₂—CH₂—O—;—O—CH₂—CH(CH₃)—O—; —O—CH(CH₃)—CH₂—O—; —O—CH₂—C(CH₂CH₂)—O—; or—O—C(CH₂CH₂)—CH₂—O—;A and B independently represent —O—; —S—; —SO—; —SO₂—;U represents aryl; heteroaryl;T represents —CONR¹—; —(CH₂)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;—(CH₂)_(p)N(R¹)SO₂—; or —COO—;Q represents lower alkylene; lower alkenylene;M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;aryl-O(CH₂)_(v)R⁵—; heteroaryl-O(CH₂)_(v)R⁵—; aryl-O(CH₂)₂O(CH₂)_(w)R⁵—;heteroaryl-(CH₂)₂O(CH₂)_(w)R⁵—;L represents —H; —CH₂OR³; —CH₂NR²R³; —CH₂NR²COR³; —CH₂NR²SO₂R³; —CO₂R³;—CH₂OCONR²R³; —CONR²R³; —CH₂NR²CONR²R³; —CH₂SO₂NR²R³; —CH₂SR³; —CH₂SOR³;—CH₂SO₂R³;R¹ represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl;cycloalkyl; aryl; cycloalkyl-lower alkyl;R² and R²′ independently represent hydrogen; lower alkyl; lower alkenyl;cycloalkyl; cycloalkyl-lower alkyl;R³ represents hydrogen; lower alkyl; lower alkenyl; cycloalkyl; aryl;heteroaryl; heterocyclyl; cycloalkyl-lower alkyl; aryl-lower alkyl;heteroaryl-lower alkyl; heterocyclyl-lower alkyl; aryloxy-lower alkyl;heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted ormono-, di- or trisubstituted with hydroxy, —OCOR², —COOR², lower alkoxy,cyano, —CONR²R²′, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH₂, —NR⁴R⁴′, or lower alkyl,with the proviso that a carbon atom is attached at the most to oneheteroatom in case this carbon atom is sp3-hybridized;R⁴ and R⁴′ independently represent hydrogen; lower alkyl; cycloalkyl;cycloalkyl-lower alkyl; hydroxy-lower alkyl; —COOR²; —CONH₂;R⁵ represents —OH, —OCOR², —COOR², —NR²R²′, —OCONR²R²′, —NCONR²R²′,cyano, —CONR²R²′, SO₃H, —SONR²R²′, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH², —NR⁴R⁴′, with theproviso that a carbon atom is attached at the most to one heteroatom incase this carbon atom is sp3-hybridized;p is the integer 1, 2, 3 or 4;r is the integer 3, 4, 5, or 6;s is the integer 2, 3, 4, or 5;t is the integer 1, 2, 3, or 4;u is the integer 1, 2, or 3;v is the integer 2, 3, or 4;w is the integer 1 or 2;and optically pure enantiomers, mixtures of enantiomers such asracemates, diastereomers, mixtures of diastereomers, diastereomericracemates, mixtures of diastereomeric racemates, and the meso-form; aswell as pharmaceutically acceptable salts, solvent complexes andmorphological forms.

In the definitions of general formula I—if not otherwise stated—the termlower alkyl, alone or in combination with other groups, means saturated,straight and branched chain groups with one to seven carbon atoms,preferably one to four carbon atoms that can be optionally substitutedby halogens. Examples of lower alkyl groups are methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andheptyl. The methyl, ethyl nad isopropyl groups are preferred.

The term lower alkoxy refers to a R—O group, wherein R is a lower alkyl.Examples of lower alkoxy groups are methoxy, ethoxy, propoxy,iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term lower alkenyl, alone or in combination with other groups, meansstraight and branched chain groups comprising an olefinic bond andconsisting of two to seven carbon atoms, preferably two to four carbonatoms, that can be optionally substituted by halogens. Examples of loweralkenyl are vinyl, propenyl or butenyl.

The term lower alkinyl, alone or in combination with other groups, meansstraight and branched chain groups comprising a triple bond andconsisting of two to seven carbon atoms, preferably two to four carbonatoms, that can be optionally substituted by halogens. Examples of loweralkinyl are ethinyl, propinyl or butinyl.

The term lower alkylene, alone or in combination with other groups,means straight and branched divalent chain groups with one to sevencarbon atoms, preferably one to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkylene areethylene, propylene or butylene.

The term lower alkenylene, alone or in combination with other groups,means straight and branched divalent chain groups comprising an olefinicbond and consisting of two to seven carbon atoms, preferably two to fourcarbon atoms, that can be optionally substituted by halogens. Examplesof lower alkenylene are vinylene, propenylene and butenylene.

The term lower alkylenedioxy, refers to a lower alkylene substituted ateach end by an oxygen atom. Examples of lower alkylenedioxy groups arepreferably methylenedioxy and ethylenedioxy.

The term lower alkylenoxy refers to a lower alkylene substituted at oneend by an oxygen atom. Examples of lower alkylenoxy groups arepreferably methylenoxy, ethylenoxy and propylenoxy.

The term halogen means fluorine, chlorine, bromine or iodine, preferablyfluorine, chlorine and bromine.

The term cycloalkyl alone or in combination, means a saturated cyclichydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which can beoptionally mono- or multisubstituted by lower alkyl, lower alkenyl,lower alkenylene, lower alkoxy, lower alkylenoxy, lower alkylenedioxy,hydroxy, halogen, —CF₃, —NR¹R¹′, —NR¹COR¹, —NR¹SO₂R¹′, —CONR¹R¹′, loweralkylcarbonyl, —COOR¹, —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R¹′ whereby R¹¹represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl;cycloalkyl; aryl; cycloalkyl-lower alkyl. The cyclopropyl group is apreferred group.

The term aryl, alone or in combination, relates to the phenyl, thenaphthyl or the indanyl group, preferably the phenyl group, which can beoptionally mono- or multisubstituted by lower alkyl, lower alkenyl,lower alkinyl, lower alkenylene or lower alkylene forming with the arylring a five- or six-membered ring, lower alkoxy, lower alkylenedioxy,lower alkylenoxy, hydroxy, hydroxy-lower alkyl, halogen, cyano, —CF₃,—OCF₃, —NR¹R¹′, —NR¹R¹′-lower alkyl, —NR¹COR¹′, NR₁SO₂R¹′, —CONR¹R¹′,—NO₂, lower alkylcarbonyl, —COOR¹, —SR¹, —SOR¹, SO₂R¹, —SO₂NR¹R¹′,benzyloxy, whereby R¹′ has the meaning given above. Preferredsubstituents are halogen, lower alkoxy, lower alkyl, CF₃, OCF₃.

The term aryloxy refers to an Ar—O group, wherein Ar is an aryl. Anexample of a lower aryloxy group is phenoxy.

The term heterocyclyl, alone or in combination, means saturated orunsaturated (but not aromatic) five-, six- or seven-membered ringscontaining one or two nitrogen, oxygen or sulfur atoms which may be thesame or different and which rings can be optionally substituted withlower alkyl, hydroxy, lower alkoxy and halogen. The nitrogen atoms, ifpresent, can be substituted by a —COOR² group. Examples of such ringsare piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl,tetrahydrofuranyl, dibydropyrrolyl, imidazolidinyl, dihydropyrazolyl,pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl.

The term heteroaryl, alone or in combination, means six-memberedaromatic rings containing one to four nitrogen atoms; benzofusedsix-membered aromatic rings containing one to three nitrogen atoms;five-membered aromatic rings containing one oxygen, one nitrogen or onesulfur atom; benzofused five-membered aromatic rings containing oneoxygen, one nitrogen or one sulfur atom; five-membered aromatic ringscontaining one oxygen and one nitrogen atom and benzofused derivativesthereof; five-membered aromatic rings containing a sulfur and a nitrogenor an oxygen atom and benzofused derivatives thereof; five-memberedaromatic rings containing two nitrogen atoms and benzofused derivativesthereof; five-membered aromatic rings containing three nitrogen atomsand benzofused derivatives thereof, or a tetrazolyl ring. Examples ofsuch ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl,pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl,thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl,isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl, quinoxalinyl.Such rings may be adequatly substituted with lower alkyl, lower alkenyl,lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy,lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen,cyano, —CF₃, —OCF₃, —NR¹R¹, —NR¹R¹′-lower alkyl, —N(R¹)COR¹,—N(R¹)SO₂R¹, —CONR¹R¹, —NO₂, lower alkylcarbonyl, —COOR¹, —SR¹, —SOR¹,—SO₂R¹, —SO₂NR¹R¹′, another aryl, another heteroaryl or anotherheterocyclyl and the like, whereby R¹′ has the meaning given above.Preferred heteroaryl are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.

The term heteroaryloxy refers to a Het-O group, wherein Het is aheteroaryl.

The term sp3-hybridized refers to a carbom atom and means that thiscarbon atom forms four bonds to four substituents placed in a tetragonalfashion around this carbon atom.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrochloric orhydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formicacid, acetic acid, maleic acid, tartaric acid, benzoic acid,methanesulfonic acid, p-toluenesulfonic acid, and the like that are nontoxic to living organisms or in case the compound of formula I is acidicin nature with an inorganic base like an alkali or earth alkali base,e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and thelike.

Compounds of the invention also include nitrosated compounds of thegeneral formula I that have been nitrosated through one or more sitessuch as oxygen (hydroxyl condensation), sulfur (sulffiydrylcondensation) and/or nitrogen. The nitrosated compounds of the presentinvention can be prepared using conventional methods known to oneskilled in the art. For example, known methods for nitrosating compoundsare described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO98/19672; WO 98/21193; WO 99/00361 and Oae et al, Org. Prep. Proc. Int.,15(3): 165-198 (1983), the disclosures of each of which are incorporatedby reference herein in their entirety.

The compounds of the general formula I can contain two or moreasymmetric carbon atoms and may be prepared in form of optically pureenantiomers, mixtures of enantiomers such as racemates, diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, and the meso-form and pharmaceuticallyacceptable salts thereof.

The present invention encompasses all these forms. Mixtures may beseparated in a manner known per se, i.e. by column chromatography, thinlayer chromatography, HPLC or crystallization.

A group of preferred compounds of general formula I above are thosewherein W, V, U, and L are as defined in general formula I and

T is —CONR¹—;

Q is methylene;

M is aryl; heteroaryl.

Another group of even more preferred compounds of general formula I arethose wherein W, U, L, T, Q, and M are as defined in general formula Iabove and

V is —CH₂CH₂O—; —CH₂CH₂CH₂O—; —OCH₂CH₂O—.

Another group of also more preferred compounds of general formula I arethose wherein V, U, T, Q, M, and L are as defined in general formula Iabove and

W represents a 1,4-disubstituted phenyl group.

Another group of also more preferred compounds of general formula I arethose wherein W, V, U, T, Q, M, and L are as defined in general formulaI above and

U is a mono-, di-, or trisubstituted phenyl or heteroaryl, wherein thesubstituents are halogen, lower alkyl, lower alkoxy, CF₃.

Especially preferred compounds of general formula I are those selectedfrom the group consisting of:

-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid    2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-hydroxyethyl)amide],-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid 7-benzylamide 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide],-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-methylpiperazine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.    I]non-2-ene-2,7-dicarboxylic acid 7-cyclopropylamide    2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide],-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-diethylamide,-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid    2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-piperidin-1-ylethyl)amide],-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-hydroxypiperidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(2-hydroxymethylpyrrolidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-aza-bicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid    2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-methoxyethyl)amide],-   (rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylic    acid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-methylamide,-   ({(rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carbonyl}amino)acetic    acid methyl ester,-   (rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carboxylic    acid,-   (rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carboxylic    acid methyl ester,-   (rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-methoxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-cyclopropoxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,3R*,5S*)-7-aminomethyl-3-{4-[3-(2-chloro-3,6-difluorophenoxy)-propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,3R*,5S*)-7-(acetylaminomethyl)-3-{4-[3-(2-chloro-3,6-difluoro-phenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide,-   (rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-dimethylaminomethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, and-   (rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-hydroxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylic    acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide.

The compounds of general formula I and their pharmaceutically acceptablesalts may be used as therapeutics e.g. in form of pharmaceuticalcompositions. These pharmaceutical compositions containing at least onecompound of general formula I and usual carrier materials and adjuvantsmay especially be used in the treatment or prophylaxis of disorderswhich are associated with a dysregulation of the renin angiotensinsystem (RAS), comprising cardiovascular and renal diseases. Examples ofsuch diseases are hypertension, congestive heart failure, pulmonaryheart failure, coronary diseases, cardiac insufficiency, renalinsufficiency, renal or myocardial ischemia, atherosclerosis, and renalfailure. They can also be used to prevent restenosis after balloon orstent angioplasty, to treat erectile dysfunction, glomerulonephritis,renal colic, and glaucoma. Furthermore, they can be used in the therapyand the prophylaxis of diabetic complications, complications aftervascular or cardiac surgery, complications of treatment withimmunosuppresive agents after organ transplantation, complications ofcyclosporin treatment, as well as other diseases presently known to berelated to the RAS.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are related to the RASsuch as hypertension, congestive heart failure, pulmonary hypertension,cardiac insufficiency, renal insufficiency, renal or myocardialischemia, atherosclerosis, renal failure, erectile dysfunction,glomerulonephritis, renal colic, glaucoma, diabetic complications,complications after vascular or cardiac surgery, restenosis,complications of treatment with immunosuppresive agents after organtransplantation, and other diseases which are related to the RAS, whichmethod comprises administering a compound according of formula I to ahuman being or animal.

The invention further relates to the use of compounds of general formulaI as defined above for the treatment and/or prophylaxis of diseaseswhich are associated with the RAS such as hypertension, congestive heartfailure, pulmonary hypertension, cardiac insufficiency, renalinsufficiency, renal or myocardial ischemia, atherosclerosis, renalfailure, erectile dysfunction, glomerulonephritis, renal colic,glaucoma, diabetic complications, complications after vascular orcardiac surgery, restenosis, complications of treatment withimmunosuppresive agents after organ transplantation, and other diseasespresently known to be related to the RAS.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with the RAS such ashypertension, coronary diseases, cardiac insufficiency, renalinsufficiency, renal and myocardial ischemia, and renal failure. Thesemedicaments may be prepared in a manner known per se.

The compounds of formula I may also be used in combination with one ormore pharmacologically active compounds e.g. with other renininhibitors, with ACE-inhibitors, angiotensin II receptor antagonists,endothelin receptor antagonists, vasodilators, calcium antagonists,potassium activators, diuretics, sympatholitics, beta-adrenergicantagonists, alpha-adrenergic antagonists, and neutral endopeptidaseinhibitors, for the treatment of disorders as above-mentioned.

All forms of prodrugs leading to an active component comprised bygeneral formula I above are included in the present invention.

The compounds of general formula I can be manufactured by the methodsoutlined below, by the methods described in the examples or by analogousmethods.

Chemistry

1,5-Dialdehydes can be prepared at best from cyclopentene derivatives(Scheme 1). Commercially available cyclopentene orcyclopent-3-enecarboxylic acid represent ideal starting materials. Ifnecessary, the substituent R^(a) can be transformed in one or severalsteps into a substituent R^(b) suitable for the preparation of the finalcompounds (→compounds of type A). Oxydation to dialdehydes of type B maybe conducted in two steps with OsO₄/NMO, then NaIO₄, or in one step withozone.

A double intramolecular Mannich condensation with at best methyl amineand 3-oxopentanedioic acid, and an aldehyde of type B, followed by adouble decarboxylation, leads to an azabicyclononene of type C (Scheme2). The R^(b)-substituent can exist both in an equatorial or in an axialposition.

Acylation of bicyclononane C can occur racemically or enantioselectivelyas described in patent application WO03/093267 (Scheme 3). Bicyclononeneof type D, whereas R^(c) is typically a methyl, an ethyl or a benzyl,can be obtained.

Then a similar chemistry may be used as described in an earlier patentapplication, and in patent applications WO03/093267 and WO04/002957. Forinstance bicyclononane D can be converted into the corresponding vinyltriflate E (Scheme 4). A suitable coupling with carbon-carbon bondformation (Suzuki, Negishi, Stille-couplings or similar ones) can leadto a bicyclononene derivative of type F, then protecting groupmanipulations can lead to a bicyclononene derivative of type G. R^(d)optionally represents any chemical precursor of a U-V group as definedin general formula I. Selective cleavage of an ester can lead to abicyclononene derivative of type H, then an amide coupling to abicyclononene derivative of type J. Standard manipulations at theR^(d)-substituent, like a Mitsunobu reaction can lead to a bicyclononenederivative of type K. If R^(b) is an ester, it can be hydrolyzed to abicyclononene derivative of type N before a desired substituent L¹ beingintroduce (→compound of type M). L₁ can be then transformed into asubstituent of type L as defined in general formula I. Finally, removalof the protecting group PG can lead to the desired final compound.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral, or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and to softgelatine capsules, solutions, emulsions or suspensions, rectally, e.g.in the form of suppositories, parenterally, e.g. in the form ofinjection solutions or infusion solutions, or topically, e.g. in theform of ointments, creams or oils.

The production of pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable acid addition salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injections are, for example, water, alcohols,polyols, glycerols and vegetable oils. Suitable carrier materials forsuppositories are, for example, natural or hardened oils, waxes, fatsand semi-liquid or liquid polyols. Suitable carrier materials fortopical preparations are glycerides, semi-synthetic and syntheticglycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquidfatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 50 mg to about 500 mg, comes into consideration.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 5-200 mg of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail.

They are, however, not intended to limit its scope in any manner.

EXAMPLES

Abbreviations

ACE Angiotensin Converting Enzyme

Ang Angiotensin

aq. aqueous

Bn Benzyl

Boc tert-Butyloxycarbonyl

BSA Bovine serum albumine

BuLi n-Butyllithium

conc. concentrated

DIPEA Diisopropylethylamine

DMAP 4-N,N-Dimethylaminopyridine

DMSO Dimethylsulfoxide

EDC HCl Ethyl-N,N-dimethylaminopropylcarbodiimide hydrochloride

EIA Enzyme immunoassay

eq. equivalent

Et Ethyl

EtOAc Ethyl acetate

FC Flash Chromatography

HOBt Hydroxybenzotriazol

KHMDS Potassium hexamethyldisilazide

MeOH Methanol

NMO N-Methylmorpholine N-oxide

org. organic

PG protecting group

Ph Phenyl

RAS Renin Angiotensin System

rt room temperature

sol. Solution

TBAF Tetra-n-butylanimonium fluoride

TBDMS tert-Butyldimethylsilyl

tBuOH tert-Butanol

tBuOK Potassium tert-butylate

Tf Trifluoromethylsulfonyl

THF Tetrahydrofuran

TLC Thin Layer Chromatography

Preparation of the Precursors

4-Oxo-2-(2-oxoethyl)butyric acid methyl ester (B)

To a sol. of cyclopent-3-enecarboxylic acid methyl ester (Lizotte, K.E.; et. al; J. Org. Chem., 1983, 48, 3594, 53 g, 0.420 mol) in MeOH (180mL) was added water (270 mL). The mixture was cooled to −10° C. andO₃/O₂ was bubbled through for 5 h, while the temperature was maintainedat −10° C. The mixture was stirred overnight under argon, while thetemperature was allowed to raise to rt. A mixture of 3,3-thiodipropionicacid (100 g, 0.560 mol) dissolved in 5M NaOH (210 mL) and 2M NaOH (35mL, final pH=7-8) was added under efficient stirring. The mixture wasstirred for 30 min, and the solvents were partially removed underreduced pressure. The residue was saturated with NaCl and extracted withEt₂O (3×). The combined org. extracts were dried over Na₂SO₄, andfiltered. Removing the solvents under reduced pressure yielded the titlecompound (42 g, 0.266 mol) as raw product that was directly engaged inthe next step.

(7r)-9-methyl-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylic acid methylester (C)

A mixture of dialdehyde B (45.5 g, 0.288 mol) in water (1.755 L) washeated to the boiling point. An emulsion formed. The mixture was allowedto cool, and conc. aq. HCl (29.7 mL) was added. The mixture was cooledto rt and kept aside. Conc. aq. HCl (71.1 mL), then NaOH (23 g) wereadded to water (5185 mL). NaOAc (222.75 g, 2.72 mol) was added. Acetonedicarboxylic acid (103.2 g, 0.671 mol) was added. Methylaminehydrochloride (59.5 g, 0.864 mol) was added. The pH was measured at 6-7.To this mixture the aldehyde mixture prepared earlier was added dropwiseover 15 min. The pH was measured at 4-4.5. The mixture was stirred for24 h. NaHCO₃ was added until the mixture was clearly basic, and themixture was saturated with Na₂SO₄. The mixture was extracted wastert-butylethylether (2×) and with butanol (2×). The ether extracts, andseparately the butanol extracts were dried over Na₂SO₄, filtered, andthe solvents were removed under reduced pressure. Purification by FC(toluene with 1% Et₃N, then EtOH) yielded the title compound (7 g, 12%).

The (7s)-isomer may have been present as minor isomer and could not beseparated. Only the major (7r)-isomer will be considered hereby.

(rac.)-(1R*,5S*,7R*)-9-Methyl-3-oxo-9-azabicyclo[3.3.1]nonane-2,7-dicarboxylicacid 2-benzyl ester 7-methyl ester (D)

A sol. of LDA was prepared from diisopropylamine (2.53 mL, 25 mmol),BuLi (1.6 M in hexanes, 15 mL, 24 mmol) and THF (75 mL). This sol. wascooled to −78° C. and a sol. of bicyclononane C (4.64 g, 22 mmol) in THF(10 mL) was added dropwise over 3 min. The reaction mixture was stirredfor 1 h at −78° C., then benzylcyanoformat (4.86 g, 30 mmol) was added.The reaction mixture was stirred for 30 min. at −78° C. The reactionmixture was quenched with acetic acid (5 g, 83 mmol), allowed to warm tort, and was partitioned between half-sat. brine (200 mL, pH 5-6) andchloroform (200 mL). The aq. phase was re-extracted with chloroform (100mL), the combined organic phases were dried over MgSO₄, filtered, andthe solvents were removed under reduced pressure. Purification of theresidue by FC (MeOH/CHCl₃ 1:30→1:25) yielded the title compound (4.22 g,56%) as an oil.

(rac.)-(1R*,5S*,7R*)-9-Methyl-3-trifluoromethanesulfonyloxy-9-azabicyclo[33.1]non-2-ene-2,7-dicarboxylicacid 2-benzyl ester 7-methyl ester (E)

A sol. of bicyclononanone D (4.20 g, 12.2 mmol) in THF (65 mL) wascooled to 0° C. and NaH (about 60% in mineral oil, 0.70 g, about 16mmol) was added. A gas evolution was observed. After 20 min, Tf₂NPh(6.35 g, 18 mmol) was added. 10 min later, the ice bath was removed. Thesol. was stirred overnight, and diluted with EtOAc and washed with brine(1×). The org. extracts were dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. Purification by FC yieldedthe title compound as an oil (4.11 g, 71%).

(rac.)-(1R*,5S*,7R*)-3-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]phenyl}-9-methyl-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 2-benzyl ester 7-methyl ester (F)

A sol. of [3-(4-bromophenyl)propoxy]-tert-butyldimethylsilane(Kiesewetter D. O., Tetrahedron Asymmetry, 1993, 4, 2183, 9.87 g, 30mmol) in THF (150 mL) was cooled to −78° C. BuLi (1.6M in hexane, 18.8mL, 30 mmol) was added. After 30 min, ZnCl₂ (1M in THF, 30 mL, 30 mmol,prepared from ZnCl₂ dried overnight at 150° C. and THF) was added. Themixture was allowed to warm up to rt. Vinyl triflate E (4.05 g, 8.48mmol) in THF (30 mL) and then Pd(PPh₃)₄ (210 mg, 0.182 mmol) were added.The mixture was heated tro reflux for 90 min and aq. 1M HCl (1 mL) wasadded. The mixture was diluted with EtOAc and washed with aq. 1M NaOH(1×). The org. extracts were dried over MgSO₄, filtered and the solventswere removed under reduced pressure. Purification of the residue by FCyielded the title product (4.54 g, 92%).

(rac.)-(1R*,5S*,7R*)-3-[4-(3-Hydroxypropyl)phenyl]-9-azabicyclo[3.3.1]non-2-ene-2,7,9-tricarboxylicacid 2-benzyl ester 9-tert-butyl ester 7-methyl ester (G)

1-Chloroethyl chloroformate (4.54 g, 32 mmol) was added to a sol. ofbicyclononene F (4.44 g, 7.7 mmol) in 1,2-dichloroethane (60 mL). Thesol. was heated to reflux. After 1 h, the reaction mixture was allowedto cool to rt, and the solvents were removed under reduced pressure.MeOH (50 mL) was added. The mixture was stirred at rt for 4 h, and thesolvents were removed under reduced pressure. The residue was dissoledin CH₂Cl₂ (30 mL), DIPEA (2.0 g, 15.5 mmol) was added, and the mixturewas cooled to 0° C. Boc₂O (1.97 g, 9.0 mmol) was added and the mixturewas stirred at rt for 2 h. The mixture was washed with aq. 1M HCl (1×),and aq. sat. NaHCO₃ (1×). The org. extracts were dried over MgSO₄,filtered, and the solvents were removed under reduced pressure.Purification of the residue by FC yielded the title compound (2.29 g,54%).

(rac.)-(1R*,5S*,7R*)-3-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7,9-tricarboxylicacid 9-tert-butyl ester 7-methyl ester (H)

A mixture of compound G (2.07 g, 3.76 mmol) and Pd/C (10%, 300 mg) inEtOAc (50 mL) was hydrogenated at rt and atmospheric pressure. Hydrogenuptake ceased after the consumption of 1 equivalent hydrogen. Themixture was filtered through a bed of Celite and the solvents wereremoved under reduced pressure to leave an oil (1.71 g, 99%). This oil(1.37 g, 9.5 mmol), TBDMS-Cl (1.00 g, 14.7 mmol) and imidazole weredissolved in CH₂Cl₂ (25 mL) and the solution stirred at rt for 6 h(TLC-control). Aq. 5% NH4Cl (50 mL) was added and the mixure extractedwith hexane (3×). The combined org. phases were dried over MgSO₄,filtered, and the solvents were removed under reduced pressure. Theresidual viscous oil (2.67 g) was dissolved in THF (35 mL), water (10mL), and methanol (10 mL). K₂CO₃ (300 mg) was added and the clearsolution stirred at rt for 1 h. 20% aq. NH₄Cl (50 mL) was added and themixture extracted with tert-butylethylether (2×). The combined org.phases were dried over MgSO₄, filtered, and the solvents were removedunder reduced pressure. The title compound (2.18 g, quantitative) wasused without further purification.

(rac.)-(1R*,3R*,5S*)-7-{4-[3-(tert-Butyldimethylsilanyloxy)-propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo[3.3.1]-non-6-ene-3,9-dicarboxylicacid 9-tert-butyl ester 3-methyl ester (J1)

A mixture of bicyclononene H (2.14 g, 3.73 mmol),cyclopropyl-(2-methyl-3-methoxybenzyl)amine (prepared by reductiveamination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J.D., J. Org. Chem., 1989, 54, 3730, and cyclopropylamine; 2.45 g, 12.8mmol), DIPEA (2.59 mL, 20 mmol), DMAP (175 mg, 1.4 mmol), HOBt (330 mg,3.9 mmol) and EDC.HCl (2.88 g, 15 mmol) in CH₂Cl₂ (35 mL) was stirred atrt for 3 days. The mixture was diluted with more CH₂Cl₂, and washed withaq. 1M HCl (3×) and aq. sat. NaHCO₃ (1×). The org. extracts were driedover MgSO₄, filtered, and the solvents were removed under reducedpressure. Purification of the residue by FC yielded the title compound(2.09 g, 75%).

(rac.)-(1R*,3R*,5S*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-7-[4-(3-hydroxypropyl)phenyl]-9-azabicyclo[3.3.1]non-6-ene-3,9-dicarboxylicacid 9-tert-butyl ester 3-methyl ester (J2)

A solution of bicyclononene J1 (2.03 g, 2.7 mmol) in THF (30 mL) wascooled in an icebath. TBAF (1M in THF, 6 mL, 6 mmol) was added and thesol. stirred at 0° C. for 15 min and at rt for 1 h. The mixture wasdiluted with tert-butylmethylether (100 mL), washed with half-sat. brine(50 mL) and sat. brine (50 mL), dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. The residual viscous oilwas purified by FC (EtOAc/hexane 2:1) to yield the title compound (1.46g, 86%).

(rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-aza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylicacid 9-tert-butyl ester 3-methyl ester (K)

Tributylphosphine (1.73 mL, 7.7 mmol) was added to a sol. ofbicyclononene J2 (1.44 g, 2.24 mmol), 2-chloro-3,6-difluorophenol (702mg, 4.3 mmol) and azodicarboxylic dipiperidide (1.16 g, 4.6 mmol) intoluene (25 mL). The mixture was heated to reflux for 2 h and allowed tocool to rt. The solvents were removed under reduced pressure.Purification by FC yielded the title compound (1.68 g, 95%).

(rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo-[3.3.1]non-6-ene-3,9-dicarboxylicacid 9-tert-butyl ester (L)

A mixture of bicyclononene K (1.68, 7.2 mmol) in aq. 1M NaOH (25 mL) andMOH (25 mL) was stirred for 5 h at rt. The mixture was allowed to coolto rt and the solvents were partially removed under reduced pressure.The residue was acidified to pH 2 with aq. 1M HCl and this mixture wasextracted with EtOAc (3×). The combined org. extracts were dried overMgSO₄, filtered, and the solvents were removed under reduced pressure.The crude title compound was used further without purification.

(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-2-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7-hydroxymethyl-9-azabicyclo[3.3.1]non-2-ene-9-carboxylicacid tert-butyl ester (M1)

A mixture of compound L (444 mg, 0.57 mmol) and LiBH4 (14.9 mg, 0.684mmol) in EtOH (5 mL) was stirred at rt overnight. The mixture wasdiluted with Et₂O, and washed with water. The org. extracts were driedover Na₂SO₄, filtered, and the solvents were removed under reducedpressure. Purifcation of the crude by FC (EtOAc/heptane 1:1) yielded thetitle compound (327 mg, 76%). LC-MS: R_(t)=1.21 min; ES+: 751.25.

(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-2-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-7-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-9-azabicyclo[3.3.1]non-2-ene-9-carboxylicacid tert-butyl ester (M2)

To a mixture of compound M1 (203 mg, 0.27 mmol) in toluene (1 mL) wereadded phthalimide (47.7 mg, 0.324 mmol), diethyl azodicarboxylic acid(62.7 μL, 0.405 mmol), and PPh₃ (142 mg, 0.54 mmol). The mixture wasstirred at rt overnight. The reaction mixture was poured over diatomaceearth (Isolute Sorbent Technology, Johnson, C. R., et al., Tetrahedron,1998, 54, 4097; 0.5 g), and was treated with aq. 1M HCl (0.6 mL). Thediatomace earth-suspension was left for 5 min, and was washed withCH₂Cl₂ (2×). The org. extracts were evaporated under reduced pressure.The residue was used without further purification. LC-MS: R_(t)=1.27min; ES+: 880.15.

(rac.)-(1R*,3R*,5S*)-7-Aminomethyl-3-{4-[3-(2-chloro-3,6-difluoro-phenoxy)propyl]phenyl}-2-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo[3.3.1]non-2-ene-9-carboxylicacid tert-butyl ester (M3)

A mixture of compound M2 (238 mg, 0.27 mmol), aq. methyl amine (41%, 2mL), and THF (2 mL) was stirred at rt for 1 h. The mixture was dilutedwith CH₂Cl₂, and washed with water. The org. extracts were dried overMgSO₄, filtered, and the solvents were removed under reduced pressure.The crude title compound was obtained as a yellow oil (323 mg), whichwas used further without purification.

EXAMPLES

General Procedure A for Amide Coupling

A sol. of the desired carboxylic acid (1.00 eq), the desired amine (3.00eq), EDC-HCl (1.50 eq.), HOBt (1.25 eq.), DMAP (cat. amount) and DIPEA(4.00 eq.) in CH₂Cl₂ (20 mL/g of acid) was stirred at rt overnight. Thereaction mixture was poured over diatomace earth (Isolute SorbentTechnology, Johnson, C. R., et al., Tetrahedron, 1998, 54, 4097),treated with aq. 1M HCl, and the org. extracts were evaporated underreduced pressure. The residue was used without further purification.

General Procedure B for the Removal of a Boc-Protecting Group

The starting material was dissolved in CH₂Cl₂ (10 mL/g of startingmaterial) and the sol. was cooled to 0° C. 4M HCl in dioxane (samevolume as CH₂Cl₂) was added and the reaction mixture was left for 2 h atrt. The solvents were removed under reduced pressure. Purification ofthe residue by HPLC led to the desired compound.

Example 1(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-hydroxyethyl)amide]

According to general procedures A and B, from bicyclononene L (0.05mmol), and 2-aminoethanol. LC-MS: 0.91 min, MH+=708.25.

Example 2(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 7-benzylamide 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]

According to general procedures A and B, from bicyclononene L (0.05mmol), and benzylamine. LC-MS: 1.00 min, MH+=754.26.

Example 3(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-methylpiperazine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

According to general procedures A and B, from bicyclononene L (0.05mmol), and N-methylpiperazine. LC-MS: 0.83 min, MH+=747.29.

Example 4(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 7-cyclopropylamide 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]

According to general procedures A and B, from bicyclononene L (0.05mmol), and cyclopropylamine. LC-MS: 0.96 min, MH+=704.27.

Example 5(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-diethylamide

According to general procedures A and B, from bicyclononene L (0.05mmol), and diethylamine. LC-MS: 0.99 min, MH+=720.27.

Example 6(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-piperidin-1-ylethyl)amide]

According to general procedures A and B, from bicyclononene L (0.05mmol), and 2-piperidin-1-ylethylamine. LC-MS: 0.85 min, MH+=775.29.

Example 7(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-hydroxypiperidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

According to general procedures A and B, from bicyclononene L (0.05mmol), and piperidin-4-ol. LC-MS: 0.92 min, MH+=748.29.

Example 8(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(2-hydroxymethylpyrrolidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

According to general procedures A and B, from bicyclononene L (0.05mmol), and pyrrolidin-2-ylmethanol. LC-MS: 0.85 min, MH+=748.28.

Example 9(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difuorophenoxy)propyl]phenyl}-9-aza-bicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-methoxyethyl)amide]

According to general procedures A and B, from bicyclononene L (0.05mmol), and 2-methoxyethylamine. LC-MS: 0.94 min, MH+=722.26.

Example 10(rac.)-(1R*,5S*,7R*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-9-aza-bicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-methylamide

According to general procedures A and B, from bicyclononene L (0.05mmol), and methyl amine hydrochloride. LC-MS: 0.94 min, MH+=678.3.

Example 11({(rac.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carbonyl}amino)aceticacid methyl ester

According to general procedures A and B, from bicyclononene L (0.05mmol), and glycine methyl ester hydrochloride. LC-MS: 0.95 min,MH+=736.25.

Example 12(rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]-non-6-ene-3-carboxylicacid

According to general procedure B, from bicyclononene L (0.05 mmol).LC-MS: 0.94 min, MH+=665.26.

Example 13(rac.)-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carboxylicacid methyl ester

According to general procedure B, from bicyclononene K (0.05 mmol).LC-MS: 0.94 min, MH+=665.26.

Example 14(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-7-methoxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

A mixture of compound M1 (37.6 mg, 0.05 mmol), MeI (4.05 μL, 0.065mmol), NaH (55%, 2.4 mg, 0.055 mmol), and 15-crown-5 (9.9 μL, 0.05 mmol)in THF (1 mL) was stirred at rt overnight. The reaction mixture waspoured over diatomace earth (Isolute Sorbent Technology, Johnson, C. R.,et al., Tetrahedron, 1998, 54, 4097; 0.5 g), and was treated with water(0.6 mL). The diatomace earth-suspension was left for 5 min, and waswashed with CH₂Cl₂ (2×). The org. extracts were evaporated under reducedpressure. The residue was used without further purification in generalprocedure B. LC-MS: 1.02 min; ES+: 665.27.

Example 15(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-7-cyclopropoxymethyl-9-aza-bicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

A mixture of compound M1 (37.6 mg, 0.05 mmol), bromomethylcyclopropane(6.21 μL, 0.065 mmol), NaH (55%, 2.4 mg, 0.055 mmol), and 15-crown-5(9.9 μL, 0.05 mmol) in THF (1 mL) was stirred at rt overnight. Thereaction mixture was poured over diatomace earth (Isolute SorbentTechnology, Johnson, C. R., et al., Tetrahedron, 1998, 54, 4097; 0.5 g),and was treated with water (0.6 mL). The diatomace earth-suspension wasleft for 5 min, and was washed with CH₂Cl₂ (2×). The org. extracts wereevaporated under reduced pressure. The residue was used without furtherpurification in general procedure B. LC-MS: 1.01 min; ES+: 705.28.

Example 16(rac.)-(1R*,3R*,5S*)-7-Aminomethyl-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

From compound M3, according to general procedure B. LC-MS: 0.82 min;ES+: 650.25.

Example 17(rac.)-(1R*,3R*,5S*)-7-(Acetylaminomethyl)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

A mixture of compound M3 (67.5 mg, 0.09 mmol), Amberlyst IRA 67 (100mg), and acetyl chloride (19.2 mL, 0.27 mmol) in CH₂Cl₂ (2 mL) wasstirred at rt overnight. Water was added, and the mixture was stirredfor 1 h. The mixture was filtered, and the filtrate was evaporated underreduced pressure. The residue was proceeded further according to generalprocedure B. LC-MS: 0.92 min; ES+: 692.27.

Example 18(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]-phenyl}-7-dimethylaminomethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

A mixture of compound M3 (135 mg, 0.18 mmol), formaldehyde (36.5% inwater, 27.6 μL, 0.36 mmol), and NaBH(OAc)₃ (53.4 mg, 0.25 mmol) inCH₂Cl₂ was stirred at rt overnight. Aq. 1M NaOH (0.2 mL) was added. Themixture was poured over diatomace earth (Isolute Sorbent Technology,Johnson, C. R., et al., Tetrahedron, 1998, 54, 4097; 0.5 g), and wastreated with aq. 1M NaOH (0.7 mL). The diatomace earth-suspension wasleft for 5 min, and was washed with CH₂Cl₂ (3×). The org. extracts wereevaporated under reduced pressure. The residue was used without furtherpurification in general procedure B. LC-MS: 0.83 min; ES+: 678.30.

Example 19(rac.)-(1R*,3R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-7-hydroxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

From compound M1, according to general procedure B. LC-MS: 0.89 min;ES+: 650.27.

Inhibition of Human Recombinant Renin by the Compounds of the Invention

The enzymatic in vitro assay was performed in 384-well polypropyleneplates (Nunc). The assay buffer consisted of 10 mM PBS (Gibco BRL)including 1 mM EDTA and 0.1% BSA. The incubates were composed of 50 μLper well of an enzyme mix and 2.5 μL of renin inhibitors in DMSO. Theenzyme mix was premixed at 4° C. and consists of the followingcomponents:

-   -   human recombinant renin (0.16 ng/mL)•synthetic human        angiotensin(1-14) (0.5 μM)    -   hydroxyquinoline sulfate (1 mM)

The mixtures were then incubated at 37° C. for 3 h.

To determine the enzymatic activity and its inhibition, the accumulatedAng I was detected by an enzyme immunoassay (EIA) in 384-well plates(Nunc). 5 μL of the incubates or standards were transferred to immunoplates which were previously coated with a covalent complex of Ang I andbovine serum albumin (Ang 1-BSA). 75 μL of Ang I-antibodies inessaybuffer above including 0.01% Tween 20 were added and a primaryincubation made at 4° C. overnight. The plates were washed 3 times withPBS including 0.01% Tween 20, and then incubated for 2 h at rt with anantirabbit-peroxidase coupled antibody (WA 934, Amersham). After washingthe plates 3 times, the peroxidase substrate ABTS(2.2′-azino-di-(3-ethyl-benzthiazolinsulfonate), was added and theplates incubated for 60 min at room temperature. After stopping thereaction with 0.1 M citric acid pH 4.3 the plate was evaluated in amicroplate reader at 405 nm. The percentage of inhibition was calculatedof each concentration point and the concentration of renin inhibitionwas determined that inhibited the enzyme activity by 50% (IC₅₀). TheIC₅₀-values of all compounds tested are below 100 nM. However selectedcompounds exhibit a very good bioavailibility and are metabolically morestable than prior art compounds.

1. Compounds of the general formula I

wherein W is a six-membered, non benzofused, phenyl or heteroaryl ring,substituted by V in meta or para position; V represents a bond;—(CH₂)_(r)—; -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t)—; —(CH₂)_(s)-A-;—(CH₂)₂-A-(CH₂)_(u)—; -A-(CH₂)_(v)—B—; —CH₂—CH₂—CH₂-A-CH₂—;-A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—B—; —CH₂—CH₂—CH₂-A-CH₂—CH₂—;—CH₂—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—CH₂—; —CH₂-A-CH₂—CH₂—B—CH₂—;—CH₂-A-CH₂—CH₂—CH₂—B—; —CH₂—CH₂-A-CH₂—CH₂—B—; —O—CH₂—CH(OCH₃)—CH₂—O—;—O—CH₂—CH(CH₃)—CH₂—O—; —O—CH₂—CH(CF₃)—CH₂—O—; —O—CH₂—C(CH₃)₂—CH₂—O—;—O—CH₂—C(CH₃)₂—O—; —O—C(CH₃)₂—CH₂—O—; —O—CH₂—CH(CH₃)—O—;—O—CH(CH₃)—CH₂—O—; —O—CH₂—C(CH₂CH₂)—O—; or —O—C(CH₂CH₂)—CH₂—O—; A and Bindependently represent —O—; —S—; —SO—; —SO₂—; U represents aryl;heteroaryl; T represents —CONR¹—; —(CH₂)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;—(CH₂)_(p)N(R¹)SO₂—; or —COO—; Q represents lower alkylene; loweralkenylene; M represents hydrogen; cycloalkyl; aryl; heterocyclyl;heteroaryl; aryl-O(CH₂)_(v)R⁵—; heteroaryl-O(CH₂)_(v)R⁵—;aryl-O(CH₂)₂O(CH₂)_(w)R⁵—; heteroaryl-(CH₂)₂O(CH₂)_(w)R⁵—; L represents—H; —CH₂OR³; —CH₂NR²R³; —CH₂NR²COR³; —CH₂NR²SO₂R³; —CO₂R³; —CH₂OCONR²R³;—CONR²R³; —CH₂NR²CONR²R³; —CH₂SO₂NR²R³; —CH₂SR³; —CH₂SOR³; —CH₂SO₂R³; R¹represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl;cycloalkyl; aryl; cycloalkyl -lower alkyl; R² and R²′ independentlyrepresent hydrogen; lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl-lower alkyl; R³ represents hydrogen; lower alkyl; lower alkenyl;cycloalkyl; aryl; heteroaryl; heterocyclyl; cycloalkyl-lower alkyl;aryl-lower alkyl; heteroaryl-lower alkyl; heterocyclyl-lower alkyl;aryloxy-lower alkyl; heteroaryloxy-lower alkyl, whereby these groups maybe unsubstituted or mono-, di- or trisubstituted with hydroxy, —OCOR²,—COOR², lower alkoxy, cyano, —CONR²R²′, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH₂, —NR⁴R⁴′ or lower alkyl,with the proviso that a carbon atom is attached at the most to oneheteroatom in case this carbon atom is sp3-hybridized; R⁴ and R⁴′independently represents hydrogen; lower alkyl; cycloalkyl;cycloalkyl-lower alkyl; hydroxy-lower alkyl; —COOR²; —CONH₂; R⁵represents —OH, —OCOR², —COOR², —NR²R²′, —OCONR²R²′, —NCONR²R²′, cyano,—CONR²R²′, SO₃H, —SONR²R²′, —CO-morpholin-4-yl,—CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH₂, —NR⁴R⁴′, with theproviso that a carbon atom is attached at the most to one heteroatom incase this carbon atom is sp3-hybridized; p is the integer 1, 2, 3 or 4;r is the integer 3, 4, 5, or 6; s is the integer 2, 3, 4, or 5; t is theinteger 1, 2, 3, or 4; u is the integer 1, 2, or 3; v is the integer 2,3, or 4; w is the integer 1 or 2; and optically pure enantiomers,mixtures of enantiomers such as racemates, diastereomers, mixtures ofdiastereomers, diastereomeric racemates, mixtures of diastereomericracemates, and the meso-form; as well as pharmaceutically acceptablesalts, solvent complexes and morphological forms.
 2. Compounds ofgeneral formula I according to claim 1 wherein W, V, U, and L are asdefined in general formula I and T represents —CONR¹—; Q representsmethylene; M represents aryl, heteroaryl; and optically pureenantiomers, mixtures of enantiomers such as racemates, diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, and the meso-form; as well as pharmaceuticallyacceptable salts, solvent complexes and morphological forms. 3.Compounds of general formula I according to claim 1 wherein W, U, L, T,Q, and M are as defined in general formula I and V represents —CH₂CH₂O—;—CH₂CH₂CH₂O—; —OCH₂CH₂O—; and optically pure enantiomers, mixtures ofenantiomers such as racemates, diastereomers, mixtures of diastereomers,diastereomeric racemates, mixtures of diastereomeric racemates, and themeso-form; as well as pharmaceutically acceptable salts, solventcomplexes and morphological forms.
 4. Compounds of general formula Iaccording to claim 1 wherein V, U, T, Q, M, and L are as defined ingeneral formula I and W represents a 1,4-disubstituted phenyl group; andoptically pure enantiomers, mixtures of enantiomers such as racemates,diastereomers, mixtures of diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates, and the meso-form; as well aspharmaceutically acceptable salts, solvent complexes and morphologicalforms.
 5. Compounds of general formula I according to claim 1 wherein W,V, Q, T, M, and L are as defined in general formula I and U is a mono-,di-, or trisubstituted phenyl or heteroaryl, whereby the substituentsare halogen, lower alkyl, lower alkoxy, CF₃ and optically pureenantiomers, mixtures of enantiomers such as racemates, diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, and the meso-form; as well as pharmaceuticallyacceptable salts, solvent complexes and morphological forms.
 6. Thecompound according to claim 1 which is(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-hydroxyethyl)amide],in free or pharmaceutically acceptable salt form.
 7. Pharmaceuticalcompositions comprising at least one compound according to claim 1 and apharmaceutically acceptable carrier.
 8. A method for the treatment orprophylaxis of diseases which are related to the renin-angiotensinsystem comprising hypertension, congestive heart failure, pulmonaryhypertension, cardiac insufficiency, renal insufficiency, renal ormyocardial ischemia, atherosclerosis, renal failure, erectiledysfunction, glomerulonephritis, renal colic, glaucoma, diabeticcomplications, complications after vascular or cardiac surgery,restenosis, complications of treatment with immunosuppressive agentsafter organ transplantation, and other diseases which are related to theRAS, which method comprises administering an effective amount of atleast one compound according to claim 1 to a human being or animal inneed of such treatment or prophylaxis.
 9. (canceled)
 10. The method ofclaim 8 further comprising administration of a pharmacologically activecompounds selected from ACE inhibitors, angiotensin II receptorantagonists, endothelin receptor antagonists, vasodilators, calciumantagonists, potassium activators, diuretics, sympatholitics,beta-adrenergic antagonists, alpha-adrenergic antagonists, and neutralendopeptidase inhibitors.
 11. A compound according to claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 7-benzylamide 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide, infree or pharmaceutically acceptable salt form.
 12. A compound accordingto claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-methylpiperazine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 13. A compound according to claim1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 7-cyclopropylamide 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide],in free or pharmaceutically acceptable salt form.
 14. A compoundaccording to claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-diethylamide, infree or pharmaceutically acceptable salt form.
 15. A compound accordingto claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-piperidin-1-ylethyl)amide],in free or pharmaceutically acceptable salt form.
 16. A compoundaccording to claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(4-hydroxypiperidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide in free orpharmaceutically acceptable salt form.
 17. A compound according to claim1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-(2-hydroxymethylpyrrolidine-1-carbonyl)-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 18. A compound according to claim1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-aza-bicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-[(2-methoxyethyl)amide],in free or pharmaceutically acceptable salt form.
 19. A compoundaccording to claim 1 which is:(1R*,5S*,7R*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2,7-dicarboxylicacid 2-[cyclopropyl-(3-methoxy-2-methylbenzyl)amide]7-methylamide, infree or pharmaceutically acceptable salt form.
 20. A compound accordingto claim 1 which is:({-(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carbonyl}amino)aceticacid methyl ester, in free or pharmaceutically acceptable salt form. 21.A compound according to claim 1 which is:(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carboxylicacid, in free or pharmaceutically acceptable salt form.
 22. A compoundaccording to claim 1 which is:(1R*,3R*,5S*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)-carbamoyl]-9-azabicyclo[3.3.1]non-6-ene-3-carboxylicacid methyl ester, in free or pharmaceutically acceptable salt form. 23.A compound according to claim 1 which is:(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-methoxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 24. A compound according to claim1 which is:(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-cyclopropoxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 25. A compound according to claim1 which is:(1R*,3R*,5S*)-7-aminomethyl-3-{4-[3-(2-chloro-3,6-difluorophenoxy)-propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 26. A compound according to claim1 which is:(1R*,3R*,5S*)-7-(acetylaminomethyl)-3-{4-[3-(2-chloro-3,6-difluoro-phenoxy)propyl]phenyl}-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclo-propyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 27. A compound according to claim1 which is:(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-hydroxymethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclopropyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 28. A compound according to claim1 which is:(1R*,3R*,5S*)-3-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-7-dimethylaminomethyl-9-azabicyclo[3.3.1]non-2-ene-2-carboxylicacid cyclo-propyl-(3-methoxy-2-methylbenzyl)amide, in free orpharmaceutically acceptable salt form.
 29. A method of making a compoundof general formula I according to claim 1 comprising deprotecting acompound of formula M:

wherein L, M, Q, T, U, V, and W are as defined for claim 1 and PG is aprotecting group, and isolating the compound of general formula I thusobtained.